tbuckley/cabot-search huggingface dataset:
Deregulation and epigenetic modification of BCL2-family genes cause resistance to venetoclax in hematologic malignancies
Authors: D. Thomalla, L. Beckmann, C. Grimm, M. Oliverio, L. Meder, C. D. Herling, P. Nieper, T. Feldmann, O. Merkel, E. Lorsy, A. da Palma Guerreiro, J. von Jan, I. Kisis, E. Wasserburger, J. Claasen, E. Faitschuk-Meyer, J. Altmüller, P. Nürnberg, T.-P. Yang, M. Lienhard, R. Herwig, K.-A. Kreuzer, C. P. Pallasch, R. Büttner, S. C. Schäfer, J. Hartley, H. Abken, M. Peifer, H. Kashkar, G. Knittel, B. Eichhorst, R. T. Ullrich, M. Herling, H. C. Reinhardt, M. Hallek, M. R. Schweiger, L. P. Frenzel
Journal: Blood (2022)

The BCL2 inhibitor venetoclax has been approved to treat different hematological malignancies. Because there is no common genetic alteration causing resistance to venetoclax in chronic lymphocytic leukemia (CLL) and B-cell lymphoma, we asked if epigenetic events might be involved in venetoclax resistance. Therefore, we employed whole-exome sequencing, methylated DNA immunoprecipitation sequencing, and genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 screening to investigate venetoclax resistance in aggressive lymphoma and high-risk CLL patients. We identified a regulatory CpG island within the PUMA promoter that is methylated upon venetoclax treatment, mediating PUMA downregulation on transcript and protein level. PUMA expression and sensitivity toward venetoclax can be restored by inhibition of methyltransferases. We can demonstrate that loss of PUMA results in metabolic reprogramming with higher oxidative phosphorylation and adenosine triphosphate production, resembling the metabolic phenotype that is seen upon venetoclax resistance. Although PUMA loss is specific for acquired venetoclax resistance but not for acquired MCL1 resistance and is not seen in CLL patients after chemotherapy-resistance, BAX is essential for sensitivity toward both venetoclax and MCL1 inhibition. As we found loss of BAX in Richter's syndrome patients after venetoclax failure, we defined BAX-mediated apoptosis to be critical for drug resistance but not for disease progression of CLL into aggressive diffuse large B-cell lymphoma in vivo. A compound screen revealed TRAIL-mediated apoptosis as a target to overcome BAX deficiency. Furthermore, antibody or CAR T cells eliminated venetoclax resistant lymphoma cells, paving a clinically applicable way to overcome venetoclax resistance.
Abstract 6081: The transcription factor SPDEF promotes the survival of mucinous pancreatic ductal adenocarcinoma of the classical subtype
Authors: Claudia Tonelli, Georgi N. Yordanov, Yuan Hao, Astrid Deschênes, Erin Brosnan, Abishek Doshi, Youngkyu Park, Jonathan Preall, David A. Tuveson
Journal: Cancer Research (2022)

Abstract Pancreatic ductal adenocarcinoma (PDA) is characterized by intra-tumoral heterogeneity. Using single-cell RNA sequencing, we reveal multiple tumor subpopulations distinguished by their differentiation state and associated with different stages of tumor progression. We identify SPDEF as a factor required for tumorigenesis in pancreatic cancer cells of epithelial and mucinous nature. SPDEF levels correlate with glandular differentiation and high secretory activity, which are characteristic features of human PDA of the classical subtype. SPDEF can drive mucus production in pancreatic cancer cells and is essential for the growth of mucus-secreting tumors by regulating endoplasmic reticulum (ER) activity. These findings offer insights into the factors controlling differentiation in PDA and may inform new therapeutic strategies with improved efficacy. Citation Format: Claudia Tonelli, Georgi N. Yordanov, Yuan Hao, Astrid Deschênes, Erin Brosnan, Abishek Doshi, Youngkyu Park, Jonathan Preall, David A. Tuveson. The transcription factor SPDEF promotes the survival of mucinous pancreatic ductal adenocarcinoma of the classical subtype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6081.
Abstract 3809: Adaptation of prostate cancer cell lines to tumor microenvironment culture conditions induces expression of androgen receptor splice variant 7 and contributes to drug resistance
Authors: Yunmin Li, Albert Wong, Ann Lu, James Lim
Journal: Cancer Research (2022)

Abstract The tumor microenvironment (TME) has several characteristics that distinguish it from normal tissue, including elevated interstitial fluid pressures and hypoxic environments. Both pressurized and hypoxic culture conditions can influence gene and protein expression of tumor cells which can result in tumor metastasis and drug resistance. Enzalutamide is effective in treating metastatic castration-resistant prostate cancer (mCRPC), but majority of patients eventually develop resistance to enzalutamide. One of the biomarkers of enzalutamide resistance is the expression of androgen receptor splice variant 7 (AR-V7), but the mechanism of how AR-V7 expression is upregulated in prostate cancer is unclear. To investigate the influence of TME culture conditions on prostate cancer cell lines, 22Rv1 and LNCaP cell lines were incubated under pressurized and hypoxic culture conditions (2 PSI + 1%O2) for a minimum of 7 days. We compared cell growth, morphology changes, gene expression profiles and drug response to enzalutamide treatment. The growth of 22Rv1 and LNCaP cells was markedly inhibited under TME culture conditions, accompanied by distinct changes in cell morphology. 22Rv1 and LNCaP cells cultured under TME conditions exhibited increased resistance to enzalutamide treatment. Higher levels of AR-V7 expression were detected in 22Rv1 and LNCaP cell lines maintained for 7 days in TME culture conditions. RNA-seq data identified 700+ genes that were differentially expressed in 22Rv1 and LNCaP cell lines adapted to TME culture conditions. GSEA analysis identified signaling pathways associated with hypoxia, glycolysis and epithelial-mesenchymal transition were upregulated under TME culture conditions, and the pathways of xenobiotic metabolism and oxidative phosphorylation were downregulated by TME culture conditions. In summary, adaptation to TME culture conditions can promote the expression of AR-V7 in prostate cancer cell lines and can contribute to enzalutamide drug resistance. Adaptation of cell lines to TME culture conditions can provide meaningful insights into mechanisms of drug resistance while providing a novel approach to identify targets and biomarkers of drug resistance. Citation Format: Yunmin Li, Albert Wong, Ann Lu, James Lim. Adaptation of prostate cancer cell lines to tumor microenvironment culture conditions induces expression of androgen receptor splice variant 7 and contributes to drug resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3809.
Publisher Correction: ILC1s control leukemia stem cell fate and limit development of AML
Authors: Zhenlong Li, Rui Ma, Shoubao Ma, Lei Tian, Ting Lu, Jianying Zhang, Bethany L. Mundy-Bosse, Bin Zhang, Guido Marcucci, Michael A. Caligiuri, Jianhua Yu
Journal: Nature Immunology (2022)
Methylome and transcriptome profiling of giant cell arteritis monocytes reveals novel pathways involved in disease pathogenesis and molecular response to glucocorticoids
Authors: Elkyn Estupiñán-Moreno, Lourdes Ortiz-Fernández, Tianlu Li, Jose Hernández-Rodríguez, Laura Ciudad, Eduardo Andrés-León, Laura Carmen Terron-Camero, Sergio Prieto-González, Georgina Espígol-Frigolé, Maria Cinta Cid, Ana Márquez, Esteban Ballestar, Javier Martín
Journal: Annals of the Rheumatic Diseases (2022)

Objectives Giant cell arteritis (GCA) is a complex systemic vasculitis mediated by the interplay between both genetic and epigenetic factors. Monocytes are crucial players of the inflammation occurring in GCA. Therefore, characterisation of the monocyte methylome and transcriptome in GCA would be helpful to better understand disease pathogenesis. Methods We performed an integrated epigenome-and transcriptome-wide association study in CD14+ monocytes from 82 patients with GCA, cross-sectionally classified into three different clinical statuses (active, in remission with or without glucocorticoid (GC) treatment), and 31 healthy controls. Results We identified a global methylation and gene expression dysregulation in GCA monocytes. Specifically, monocytes from active patients showed a more proinflammatory phenotype compared with healthy controls and patients in remission. In addition to inflammatory pathways known to be involved in active GCA, such as response to IL-6 and IL-1, we identified response to IL-11 as a new pathway potentially implicated in GCA. Furthermore, monocytes from patients in remission with treatment showed downregulation of genes involved in inflammatory processes as well as overexpression of GC receptor-target genes. Finally, we identified changes in DNA methylation correlating with alterations in expression levels of genes with a potential role in GCA pathogenesis, such as ITGA7 and CD63 , as well as genes mediating the molecular response to GC, including FKBP5, ETS2 , ZBTB16 and ADAMTS2 . Conclusion Our results revealed profound alterations in the methylation and transcriptomic profiles of monocytes from GCA patients, uncovering novel genes and pathways involved in GCA pathogenesis and in the molecular response to GC treatment.
Associations of Obesity, Physical Activity, and Screening With State-Level Trends and Racial and Ethnic Disparities of Breast Cancer Incidence and Mortality in the US
Authors: Zhaomin Xie, Wei Xie, Yuanke Liang, Haoyu Lin, Jundong Wu, Yukun Cui, Xuefen Su, De Zeng
Journal: JAMA Network Open (2022)

<h3>Importance</h3> Breast cancer causes disproportionate disease burden among various racial and ethnic groups in the US. However, state-level temporal trends and racial and ethnic disparities and whether metabolic and lifestyle factors and screening access are associated with temporal changes remain largely unknown. <h3>Objectives</h3> To investigate temporal trends and racial and ethnic variations at the state level and ecological correlations between obesity, physical activity, and mammography screening and breast cancer incidence and mortality trends among women in the US. <h3>Design, Setting, and Participants</h3> A cross-sectional study was conducted to analyze breast cancer incidence and mortality trends among women in the US from January 1, 1999, to December 31, 2017, whereas an ecological analysis was performed to assess the associations. Data were analyzed from March 1, 2021, to September 30, 2021. Population-based cancer registry data were obtained from US Cancer Statistics incidence and mortality data. Prevalence of obesity, physical activity, and mammography screening were obtained from the Behavioral Risk Factor Surveillance System. <h3>Exposures</h3> Prevalence of obesity, physical activity, and mammography screening. <h3>Main Outcomes and Measures</h3> Breast cancer incidence and mortality trends from 1999 to 2017 in the 50 US states and the District of Columbia. <h3>Results</h3> A total of 4 136 123 breast cancer cases and 782 454 deaths were included in the analysis, with a significant reduction in incidence (average annual percent change [AAPC], −0.4% [95% CI, −0.6% to −0.2%)]) and mortality (AAPC, −1.7% [95% CI, −1.8% to −1.5%]) during the study period. A significant state-level variation in breast cancer incidence and mortality between White women and those of other races and ethnicities was observed. A significant positive correlation was found between obesity and breast cancer incidence (<i>r</i> = 0.316;<i>P</i> = .02) and mortality (<i>r</i> = 0.400;<i>P</i> = .004) and an inverse correlation was found between physical activity and incidence (<i>r</i> = −0.577;<i>P</i> &lt; .001) in women 55 years or older and mammography screening and mortality trends (<i>r</i> = −0.644;<i>P</i> &lt; .001) in women 40 years or older. <h3>Conclusions and Relevance</h3> The findings of this cross-sectional study suggest that racial and ethnic disparities exist at the state level with regard to breast cancer incidence and mortality among women in the US. Metabolic and lifestyle factors and screening access were associated with the observed trends and racial and ethnic disparities. Interventions targeting these factors may help reduce the incidence of breast cancer and related deaths.
Abstract 5866: Racial ethnic variations in trajectory of health-related quality of life in older women with breast cancer
Authors: Sushantti Rupesh, Eunkyung Lee
Journal: Cancer Research (2022)

Abstract The purpose of the research study was to explore the ethnic/racial variations in health-related quality of life (HRQoL) scores, and the trajectory of comorbidities in older women with breast cancer. This study analyzed data from the Surveillance, Epidemiology, and End-Results (SEER) – Medicare Health Outcomes Survey (MHOS) linked data resource. The study population consists of 982 women (≥ 65 years old at diagnosis) with primary breast cancer who were diagnosed in 1998-2012 and completed the MHOS survey within 24 months before diagnosis and completed at least one more survey after diagnosis. The study population was grouped into three ethnic/racial groups: Whites (n=791), Black/African American (n=104) and Hispanics (n=87). The mean age of the population was 74.8 ± 6.1. HRQoL was measured using SF-36/VR-12 questionnaire and summarized as Physical Component Summary (PCS) Score and a Mental Component Summary (MCS) Score. Results showed an increase in the PCS score at month 6 after diagnosis, and a decrease at month 12 was observed in Whites and Black/African Americans. A continuous decrease in the PCS score till month 12 and an increase at month 24 was observed in Hispanics. All three groups showed similar trends in MCS scores over time - the MCS score dropped at month 6 but was back at baseline by month 12. The Whites had the highest MCS score out of the three, and Hispanics had the lowest. The MCS score for Hispanics decreased by month 36, whereas it increased for Black/African Americans. The MCS score for Whites remained fairly the same. The results also showed an increase in the total number of comorbidities at month six after diagnosis, along with a decrease to the baseline comorbidities by month 12. Hispanics had the highest increase in comorbidities at month 6 and Whites had the lowest and most stable. The number of comorbidities remained fairly the same in Whites and Black/African Americans, whereas the number of comorbidities increased slightly at month 24 for Hispanics and drastically increased at month 36. Overall, changes in the total number of comorbidities had a negative correlation with the changes in MCS scores, therefore it can be concluded that the number of comorbidities have a negative effect on a patient’s mental health. Whites were observed to have less comorbidities and better MCS scores than Black/African Americans or Hispanics. The information gained from this study will help clinicians and patients in the shared treatment decision process and guide individualized survivorship care plans among older women with breast cancer. Citation Format: Sushantti Rupesh, Eunkyung Lee. Racial ethnic variations in trajectory of health-related quality of life in older women with breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5866.
Abstract 3563: CD8+ T cell-mediated tumor rejection by an Adeno-associated virus-like particle (AAVLP) vaccine
Authors: Lasse Neukirch, Patrick Schmidt, Inka Zörnig, Dirk Jäger, Silke Uhrig-Schmidt
Journal: Cancer Research (2022)

Abstract The utilization of adeno-associated viruses (AAVs) as vaccines has primarily been focused on the induction of antibody responses. Displaying antigens derived from HER2 or HPV on the AAV capsid surface lead to strong humoral immune responses. However, the potential of AAVs as T cell inducing vaccines has been poorly investigated. Model antigens have been inserted into the capsid of AAVs to analyze T cell responses, but these studies rather focused on preventing vector immunity for an improved tolerance of gene therapies. By using this as a starting point, we set out to test AAVs as T cell inducing vaccines with the prospect of targeting cancer neoantigens. In first experiments, the general properties of the vaccination strategy were estimated by displaying the ovalbumin-derived model antigen SIINFEKL on the surface of adeno-associated virus-like particles (AAVLPs). Upon injection of the AAVLP-SIINFEKL vaccine, mice developed strong CD8+ T cell responses against the displayed antigen. Highest immune responses were achieved by subcutaneous hock injection of AAVLPs, adjuvanted by Montanide ISA 51 VG. SIINFEKL-specific T cell responses peaked around three weeks after vaccination, whereas a memory subset remained present for long term. The anti-tumor efficacy of the vaccine was shown by injecting SIINFEKL-expressing B16F10 melanoma cells subcutaneously into mice, in which the tumor was completely rejected after vaccination. Interestingly, the induction of CD8+ T cell responses and the tumor protection depended on the presence of CD4+ T cells. Accordingly, T helper epitopes were identified in the AAVLP capsid sequence. In addition to the initial tests, a set of murine neoantigens, derived from B16F10 cells, were displayed on AAVLPs. In direct comparison to a peptide vaccine, which did not have an effect on tumor growth, the AAVLP vaccine had a significant impact on the tumor growth rate. In conclusion, AAVLPs show promising effects as T cell vaccines. The vaccination strategy can be used to induce cytotoxic T cell responses in general and anti-tumor effects in particular. AAV capsid-specific helper epitopes is one inherent advantage, since the AAVLP vaccine delivers immune stimulation within the viral particle itself. Thus, antigen-displaying AAVLPs could be an alternative to current gold standards in the field of neoantigen vaccines and have a prospect for future clinical applications. Citation Format: Lasse Neukirch, Patrick Schmidt, Inka Zörnig, Dirk Jäger, Silke Uhrig-Schmidt. CD8+ T cell-mediated tumor rejection by an Adeno-associated virus-like particle (AAVLP) vaccine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3563.
Chronologically modified androgen receptor in recurrent castration-resistant prostate cancer and its therapeutic targeting
Authors: Mithila Sawant, Kiran Mahajan, Arun Renganathan, Cody Weimholt, Jingqin Luo, Vandna Kukshal, Joseph M. Jez, Myung Sik Jeon, Bo Zhang, Tiandao Li, Bin Fang, Yunting Luo, Nicholas J. Lawrence, Harshani R. Lawrence, Felix Y. Feng, Nupam P. Mahajan
Journal: Science Translational Medicine (2022)

Resistance to second-generation androgen receptor (AR) antagonists such as enzalutamide is an inevitable consequence in patients with castration-resistant prostate cancer (CRPC). There are no effective therapeutic options for this recurrent disease. The expression of truncated AR variant 7 (AR-V7) has been suggested to be one mechanism of resistance; however, its low frequency in patients with CRPC does not explain the almost universal acquisition of resistance. We noted that the ability of AR to translocate to nucleus in an enzalutamide-rich environment opens up the possibility of a posttranslational modification in AR that is refractory to enzalutamide binding. Chemical proteomics in enzalutamide-resistant CRPC cells revealed acetylation at Lys 609 in the zinc finger DNA binding domain of AR (acK609-AR) that not only allowed AR translocation but also galvanized a distinct global transcription program, conferring enzalutamide insensitivity. Mechanistically, acK609-AR was recruited to the AR and ACK1/TNK2 enhancers, up-regulating their transcription. ACK1 kinase–mediated AR Y267 phosphorylation was a prerequisite for AR K609 acetylation, which spawned positive feedback loops at both the transcriptional and posttranslational level that regenerated and sustained high AR and ACK1 expression. Consistent with these findings, oral and subcutaneous treatment with ACK1 small-molecule inhibitor, ( R )-9b, not only curbed AR Y267 phosphorylation and subsequent K609 acetylation but also compromised enzalutamide-resistant CRPC xenograft tumor growth in mice. Overall, these data uncover chronological modification events in AR that allows prostate cancer to evolve through progressive stages to reach the resilient recurrent CRPC stage, opening up a therapeutic vulnerability.
Abstract 5313: A BCL-XL PROTAC degrader DT2216 synergizes with KRASG12C inhibitors for effectively treating KRASG12C-mutated cancers
Authors: Sajid Khan, Janet Wiegand, Peiyi Zhang, Wanyi Hu, Dinesh Thummuri, Vivekananda Budamagunta, Nan Hua, Lingtao Jin, Carmen J. Allegra, Edmund S. Kopetz, Maria Zajac-Kaye, Frederic J. Kaye, Guangrong Zheng, Daohong Zhou
Journal: Cancer Research (2022)

Abstract Purpose: Mutations in KRAS are the most common oncogenic drivers. Sotorasib (AMG510), a covalent inhibitor selectively targeting KRASG12C, was recently approved for the treatment of KRASG12C-mutated non-small cell lung cancer (NSCLC). However, the clinical efficacy of sotorasib and other KRASG12C inhibitors is limited by intrinsic resistance in colorectal cancer (CRC) and by the rapid emergence of acquired resistance in all treated solid tumors. Therefore, there is an urgent need to develop novel combination therapies to overcome sotorasib resistance and to maximize its efficacy. Experimental Design: A panel of KRASG12C-mutated cell lines from NSCLC, CRC and pancreatic cancer (PC) were treated with sotorasib alone or in combination with BCL-XL proteolysis targeting chimera (PROTAC, such as DT2216) to assess effects on cell viability, colony formation and apoptosis. To identify mechanisms underlying sotorasib+DT2216 combination responses, we analyzed KRAS downstream signaling and expression of BCL-2 family proteins, and performed co-immunoprecipitation of BCL-XL to evaluate its interaction with pro-apoptotic BH3-only proteins. Finally, therapeutic efficacy of sotorasib alone and in combination with DT2216 was evaluated in vivo using different tumor xenograft models. Results: We observed heterogeneous responses to sotorasib alone, whereas its combination with DT2216 strongly inhibited viability of KRASG12C cell lines that partially responded to sotorasib treatment. Mechanistically, co-treatment with DT2216 inhibited sotorasib-induced BCL-XL/BIM interaction leading to enhanced apoptosis. Furthermore, DT2216 co-treatment significantly improved the antitumor efficacy of sotorasib in vivo. Conclusions: Our findings suggest that due to cytostatic activity, the efficacy of sotorasib is limited, and therefore its combination with a pro-apoptotic agent DT2216 shows synergistic responses and can potentially overcome resistance. Citation Format: Sajid Khan, Janet Wiegand, Peiyi Zhang, Wanyi Hu, Dinesh Thummuri, Vivekananda Budamagunta, Nan Hua, Lingtao Jin, Carmen J. Allegra, Edmund S. Kopetz, Maria Zajac-Kaye, Frederic J. Kaye, Guangrong Zheng, Daohong Zhou. A BCL-XL PROTAC degrader DT2216 synergizes with KRASG12C inhibitors for effectively treating KRASG12C-mutated cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5313.